Symmetric and Mixed Amino Acid Anhydrides

Although dicyclohexylcarbodiimide activation to date is still the widely used coupling method on polymer phase, we searched for an alternate to circumvent all the problems combined with diimide side reactions and the formation of the scarcely soluble dicyclohexylurea. For this purpose we reinvestigated the direct synthesis of synunetric anhydrides from N-protected amino acids with phosgene [142-145] (Fig. 43). 

By the aid of a modified peptide synthesizer solutions of two moles of Boc- or Ddz-amino acid salts (sodium- or triethylammonium form) in tetrahydrofuran or dichloro-methane at —40 °C are mixed for 5 minutes with one mole of phosgene in the same solvent at —40 °C, controlled by the punched tape program of the synthesizer (Fig. 44). The solution of the symmetric anhydride is added at —40 C to the gel polymer, which is contained in the centrifugal reactor (see p. 75) and is allowed to warm up to the cooling water temperature level (9—13 C) of the reactor during the peptide synthesis period of 30 minutes. Since the mode of action of the centrifugal reactor renders it possible to perfuse an external IR flow cell with the reaction solution, we are in a position to monitor directly the quality of the symmetric anhydride and its consumption, watching the characteristic absorptions on 1,830 and 1,760 cm [71]. In several cases the symmetric anhydrides were isolated in crystalline or solid form for characterization (Table 6). 

The most secure procedure for the clean preparation of symmetric anhydrides was found in the use of a 10% excess of free carboxylic component over its triethylammonium salt and a 10% excess of this salt over the equivalents of phosgene added at —40 C. 

Impure IR spectra of synunetric anhydrides (Fig. 45), particularly in the range of 1,690 and 1,800 cm , show absorption bands which might be allied to Leuch s anhydrides [146, 147] (excess phosgene) and N-acyl-aziridinones [148] (excess triethylamine). Though the latter was demonstrated to be the highly reactive racemization-free precursor of both the intramolecular asymmetric and the intermolecular symmetric anhydride, the tendency for racemization of the Leuch s compound during reaction with the gel-phase-bound amino component has to be considered. In two cases even a distinct dependence on the salt cation of the carboxylic component in the formation of the possible side products mentioned was observed. Exclusively thb sodium salts of Ddz-valine and Ddz-(tert. butyl)- 

Nucleophilic centers of trifunctional carboxylic components naturally have to be masked before the formation of synunetric anhydrides. Ddz-tryptophane, for example, shows several side reactions with phosgene, whereas the same compound with formyl masked indole nitrogen results in an excellently pure symmetric anhydride [71] (Fig. 46). 

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